The present invention relates to pharmaceutical compositions containing N-acetyl-p-aminophenol, known by the generic names paracetamol, acetaminophen and APAP (hereinafter referred to as paracetamol). In particular, the invention relates to a fast acting paracetamol formulation containing a small amount of antacid, the formulation being in the form of a swallow tablet or capsule or other like dosage form.
Paracetamol is a commonly used analgesic and antipyretic drug that has been available in many countries for more than 40 years. A wealth of experience clearly establishes it as the standard antipyretic and analgesic for mild to moderate pain states. However it is known that following ingestion of paracetamol in solid form, e.g. as a tablet or capsule, rate of drug absorption, and hence onset of pharmacological activity, may vary from patient to patient. Recently it has been reported that absorption of paracetamol in tablet form is greatly affected by food and that maximum plasma concentrations of paracetamol are not always reached, which could have implications for pain relief in some patients (Stillings M. et al, Current Medical Research and Opinion 16(2):115-124, 2000).
In the past, attempts have been made to improve paracetamol absorption, for example by the use of soluble paracetamol tablets. Such tablets have been shown to have a faster rate of absorption (Rygnestad T et al., Eur J Clin Pharmacol 56: 141-143, 2000) and a faster onset of analgesic action compared to conventional paracetamol tablets (Moeller P L. et al., J Clin Pharmacol. 40: 370-378, 2000). However soluble tablets are not always convenient as they have to be dissolved in water prior to administration and moreover paracetamol-containing solutions may be unpalatable to some patients.
According to United Kingdom patent publication GB 2 103 087 (Bristol-Myers), an improved rate of absorption is achieved by co-administering a therapeutic dose comprising from about 150 mg to about 2000 mg of paracetamol with from about 60 mg to about 1200 mg of an antacid. A preferred range of antacid is disclosed as being from about 400 mg to about 1000 mg with a so-called optimum range being from about 450 mg to 880 mg. GB 2 103 087 reports that when the various formulations exemplified therein were administered to healthy volunteers in the fasted state, it was found that the actual increase in rate of absorption was between 7 and 31% compared to conventional paracetamol tablets.
WO 98/38983 (SmithKline Beecham) reports that a tablet or capsule formulation containing a combination of sodium bicarbonate and paracetamol, wherein the paracetamol is present in an amount of at least 300 mg and the weight ratio of bicarbonate to paracetamol is at least 0.74 to 1, gives a statistically significant improvement in the rate of absorption over that obtained from a commercially available paracetamol tablet containing no sodium bicarbonate.
According to Grattan et al, (Grattan T. et al, Eur J Pharm Biopharm. 43(3): 225-229, 2000) compositions comprising 400 mg or 630 mg sodium bicarbonate increase the rate of absorption of paracetamol relative to conventional paracetamol tablets in fasted healthy volunteers. The authors suggest that the effect of sodium bicarbonate on paracetamol absorption may be dose dependent.
WO02/36101 (Laboratorios Belmac S.A.) discloses a galenic formulation comprising a basic mixture of paracetamol and citric acid, a weak alkali such as sodium bicarbonate/sodium carbonate, sodium citrate on its own or mixed with other salts of weak organic acids and a pharmaceutically acceptable carrier. It is intended in WO02/36101 to provide a formulation that is both dispersible and soluble in water. The alkali is included for the purpose of increasing pH, which would otherwise be too low for use in highly dispersible soluble tablets. There is no disclosure or teaching of how to improve paracetamol absorption following ingestion of a paracetamol-containing solid dosage form designed to be swallowed.